Divergent Synthesis Research Articles

Expanding Natural Diversity: Tailored Enrichment of the 8,12-Sesquiterpenoid Lactone Chemical Space through Divergent Synthesis.

The divergent synthesis of a non-natural 8,12-sesquiterpenoid lactone collection is described. The synthesis relies on a rationally designed guaianolide scaffold bearing a tertiary hydroxyl as the pinpoint for inducing its selective diversification. Key reactions include an unprecedented Suarez-type CH lactonization and a highly diastereoselective oxy-Cope/ene cascade that allows the introduction of three stereocenters in a single operation. Selective oxidative/reductive and redox neutral transformations follow to highlight the synthesis of naturally unpresented highly substituted 8,12-guaianolides.

Divergent Synthesis of Pyrazoles via Manganese Pincer Complex Catalyzed Acceptorless Dehydrogenative Coupling Reactions.

This report detailed the synthesis of multi-substituted pyrazoles through the acceptorless dehydrogenative coupling (ADC) reaction catalyzed by a well-defined manganese(I)-pincer complex. Symmetrically substituted pyrazoles were synthesized by reacting 1,3-diols with hydrazines. Unsymmetrically substituted pyrazoles were selectively made via the ADC of primary alcohols with methyl hydrazones. Water and hydrogen are liberated as the green byproducts. The endurance of these methodologies has been presented by producing 30 substrates with varied functionalities. Model reactions were scaled up to demonstrate practicability. The reaction rate and order were measured to transparent the involvement of the reagents during catalysis. Control experiments elucidated the plausible reaction mechanisms.

Eudistomins Y-Inspired Design and Divergent Optimization of Heteroaryl Ketones for New Antifungal Leads.

The discovery of structurally distinct leads is imperative in modern agrochemical science. Inspired by eudistomins Y and the framework-related pharmaceuticals, aryl heteroaryl ketone was drawn as a common model intriguing the design and divergent synthesis of 14 kinds of heteroaryl ketones aligned with their oxime derivatives. Antifungal function-oriented phenotypical screen protruded benzothiazolyl-phenyl oxime 5a as a promising model, and the concomitant modification led to benzothiazolyl oxime 5am (EC50 = 5.17 μM) as a superior lead than fluoxastrobin (EC50 = 7.54 μM) against Sclerotinia sclerotiorum. Scaffold hopping of the phenyl subunit identified benzothiazolyl-pyridyl oxime as a novel antifungal scaffold accompanied by acquiring oxime 5bm with remarkable activity (EC50 = 3.57 μM) against Pyricularia oryzae. Molecular docking showed that candidate 5am could form more hydrogen bonds with the amino acid residues of actin than metrafenone. This compound also demonstrated better curative efficacy than that of fluoxastrobin and metrafenone in controlling the plant disease caused by S. sclerotiorum. These results rationalize the discovery of antifungal candidates based on aryl heteroaryl ketone.

Divergent Synthesis of Cyclopropanated Tetrahydroquinolines by Tandem Functionalization of Quinoline Derivatives.

Here, reported is a new method for divergent synthesis of functionalized tetrahydroquinolines (THQs), featuring a biomedically interesting azabicyclo[4.1.0]heptane core, proceeding with mild conditions, good substrate and functionality tolerance, and operational simplicity. Mechanistic studies suggest that the products are formed via carbonucleophilic 1,4-addition-induced dearomatization of quinolinium salts and intramolecular cyclopropanation with α-halo ketones followed by α-nucleophilic addition with different nucleophiles. The present work lays a foundation to access new N-heterocycles via the dearomative tandem functionalization of azaarenes.

4 + 2] Cyclization or Lossen Rearrangement: Rhodium-Catalyzed Divergent Synthesis of Carboline Derivatives with Anticancer Activity.

An unusual rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition tandem cyclization has been achieved along with a tunable well-known C-H activation/[4 + 2] annulation, leading to regio-, chemo-, and diastereoselective access to diverse pentacyclic α-carbolines and β-carboline-1-one derivatives in moderate to good yields with significant anticancer activity.

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes.

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order cycloaddition and catalytic asymmetric cycloaddition of BCBs have been long-standing formidable challenges. Here, we report Pd-catalyzed ligand-controlled, tunable cycloadditions for the divergent synthesis of bridged bicyclic frameworks. The dppb ligand facilitates the formal (5+3) cycloaddition of BCBs and vinyl oxiranes, yielding valuable eight-membered ethers with bridged bicyclic scaffolds in 100% regioselectivity. The Cy-DPEphos ligand promotes selective hetero-[2σ+2σ] cycloadditions to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, the corresponding catalytic asymmetric synthesis of O-BCHeps with 94-99% ee has been achieved using chiral (S)-DTBM-Segphos, representing the first catalytic asymmetric cross-dimerization of two strained rings. The obtained O-BCHeps are promising bioisosteres for ortho-substituted benzenes.

Switchable divergent synthesis of chiral indole derivatives via catalytic asymmetric dearomatization of 2,3-disubstituted indoles.

A strategy allowing the switchable divergent synthesis of chiral indole derivatives was established via chiral phosphoric acid-catalyzed asymmetric dearomatization of 2,3-disubstituted indoles using naphthoquinone monoimines as electrophiles. The products were switched between chiral indolenines and fused indolines according to the post-processing conditions. Both two types of products were obtained in good to high yields with generally excellent enantioselectivities. NaBH4 was found to work as a promoter as well as a reductant in the cyclization process leading to fused indolines.

Divergent Synthesis of 5,7-Diazaullazines Derivatives through a Combination of Cycloisomerization with Povarov or Alkyne-Carbonyl Metathesis.

Ullazines and their π-expanded derivatives have gained much attention as active components in various applications, such as in organic photovoltaic cells or as photosensitizers for CO2 photoreduction. Here, we report the divergent synthesis of functionalized diazaullazines by means of two different domino-reactions consisting of either a Povarov/cycloisomerization or alkyne-carbonyl metathesis/cycloisomerization protocol. The corresponding quinolino-diazaullazine and benzoyl-diazaullazine derivatives were obtained in moderate to good yields. Their optical and electronic properties were studied and compared to related, literature-known compounds to obtain insights into the impact of nitrogen doping and π-expansion.

Divergent Synthesis of Scabrolide A and Havellockate via an exo-exo-endo Radical Cascade.

Here we report a concise and divergent synthesis of scabrolide A and havellockate, representative members of polycyclic marine natural product furano(nor)cembranoids. The synthesis features a highly efficient exo-exo-endo radical cascade. Through the generation of two rings, three C-C bonds, and three contiguous stereocenters in one step, this remarkable transformation not only assembles the bowl-shaped, common 6-5-5 fused ring system from simple building blocks but also precisely installs the functionalities at desired positions and sets the stage for further divergent preparation of both target molecules. Further studies reveal that the robust and unusual 6-endo radical addition in the cascade is likely facilitated by the rigidity of the substrate.

Access to Reverse Glycosyl Azides and Rare Sugar-Based Glycosyl Azides via Radical Decarboxylative Azidation: Divergent Synthesis of 4'-C-Azidonucleosides as Potential Antiviral Agents.

The radical decarboxylative azidation of structurally diverse uronic acids has been established as an efficient approach to reverse glycosyl azides and rare sugar-derived glycosyl azides under the action of Ag2CO3, 3-pyridinesulfonyl azide, and K2S2O8. The power of this method has been highlighted by the divergent synthesis of 4'-C-azidonucleosides using Vorbrüggen glycosylation of nucleobases with 4-C-azidofuranosyl acetates. The antiviral assessment of the resulting nucleosides revealed one compound as a potential inhibitor of covalently closed circular DNA.

Enantioselective Tsuji‐Trost α‐Fluoroallylation of Amino Acid Esters with Gem‐Difluorinated Cyclopropanes

AbstractA novel enantioselective Tsuji–Trost‐type cross coupling reaction between gem‐difluorinated cyclopropanes and N‐unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity‐oriented synthesis (DOS) of optically active α‐quaternary α‐amino acid esters bearing a linear 2‐fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non‐covalent interactions between the Pd(II)‐π‐fluoroallyl species and the Ni(II)‐Schiff base complex.

Enantioselective Tsuji-Trost α-Fluoroallylation of Amino Acid Esters with Gem-Difluorinated Cyclopropanes.

A novel enantioselective Tsuji-Trost-type cross coupling reaction between gem-difluorinated cyclopropanes and N-unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity-oriented synthesis (DOS) of optically active α-quaternary α-amino acid esters bearing a linear 2-fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non-covalent interactions between the Pd(II)-π-fluoroallyl species and the Ni(II)-Schiff base complex.

Intramolecular Palladium(II)-Catalyzed Regioselective 6-endo or 6-exo C-H Benzannulation: An Approach for the Diversity-Oriented Synthesis of Quinolinone Derivatives from Pyridones.

Herein, a new intramolecular palladium(II)-catalyzed regioselective 6-endo-trig or 6-exo-trig annulation through direct C-H activation is presented as a method for the diversity-oriented synthesis of highly substituted quinolinones from pyridones. The reaction occurs under mild conditions and exhibits excellent regioselectivity, good functional group tolerance, and broad applications. This innovative approach has been successfully utilized in the synthesis of Glycopentanolone A and an intermediate of (R)-(+)-Tipifarnib.

Diversified Synthesis of Chiral Fluorinated Cyclobutane Derivatives Enabled by Regio- and Enantioselective Hydroboration.

The diversified synthesis of chiral fluorinated cyclobutane derivatives has remained a difficult task in synthetic chemistry. Herein, we present an approach for asymmetric hydroboration and formal hydrodefluorination of gem-difluorinated cyclobutenes through rhodium catalysis, providing chiral gem-difluorinated α-boryl cyclobutanes and monofluorinated cyclobutenes with excellent regio- and enantioselectivity, respectively. The key to the success of the two transformations relies on an efficient, mild and highly selective rhodium-catalyzed asymmetric hydroboration with HBPin (pinacolborane), in which the subsequent addition of a base, and a catalytic amount of palladium in some cases, results in the formation of formal hydrodefluorination products with the four-membered ring retained. The obtained chiral gem-difluorinated α-boryl cyclobutanes are versatile building blocks that provide a platform for the synthesis of enantioenriched fluorinated cyclobutane derivatives to a great diversity.

Diversified Synthesis of Chiral Fluorinated Cyclobutane Derivatives Enabled by Regio‐ and Enantioselective Hydroboration

AbstractThe diversified synthesis of chiral fluorinated cyclobutane derivatives has remained a difficult task in synthetic chemistry. Herein, we present an approach for asymmetric hydroboration and formal hydrodefluorination of gem‐difluorinated cyclobutenes through rhodium catalysis, providing chiral gem‐difluorinated α‐boryl cyclobutanes and monofluorinated cyclobutenes with excellent regio‐ and enantioselectivity, respectively. The key to the success of the two transformations relies on an efficient, mild and highly selective rhodium‐catalyzed asymmetric hydroboration with HBPin (pinacolborane), in which the subsequent addition of a base, and a catalytic amount of palladium in some cases, results in the formation of formal hydrodefluorination products with the four‐membered ring retained. The obtained chiral gem‐difluorinated α‐boryl cyclobutanes are versatile building blocks that provide a platform for the synthesis of enantioenriched fluorinated cyclobutane derivatives to a great diversity.

Copper(I)-Catalyzed Indolyl Ynamide Oxidation/Dearomatization: Divergent and Regioselective Synthesis of Valuable Indoline Scaffolds.

A highly convenient copper(I)-catalyzed oxidation-initiated cyclopropanation of indolyl ynamide for the rapid construction of indole-fused cyclopropane-lactams is described, which represents, to the best of our knowledge, the first non-noble-metal-catalyzed indolyl ynamide oxidation/dearomatization by the in situ generated α-oxo copper carbenes. Compared to hydrazone and diazo, the use of alkynes as carbene precursors allows cyclopropanation to occur under a safe and convenient pathway. Moreover, this transformation can lead to the divergent synthesis of pentacyclic spiroindolines involving the reversal of ynamide regioselectivity by engineering substrate structures.

Palladium-Catalyzed Divergent Enantioselective Functionalization of Cyclobutenes.

Aliphatic strained rings have been increasingly applied in medicinal chemistry due to their beneficial physicochemical and pharmacokinetic properties. However, the divergent synthesis of enantioenriched cyclobutane derivatives with various structural patterns continues to be a significant challenge. Here, we disclose a palladium-catalyzed enantioselective desymmetrization of cyclobutenes, resulting in a series of hydroarylation and 1,2- and 1,3-diarylation products via the interceptions of a common Heck intermediate. Mechanistic investigations provide valuable insights into understanding the catalytic mode of the palladium catalysts and the observed variations in the deuterium-responsive behavior during reactions. Furthermore, the synthetic utility is demonstrated in the syntheses of deuterated drug candidate belaperidone skeletons and pseudosymmetrical truxinic acid-type derivatives.

Decoding the Structural Diversity: A New Horizon in Antimicrobial Prospecting and Mechanistic Investigation.

The escalating crisis of antimicrobial resistance (AMR) underscores the urgent need for novel antimicrobials. One promising strategy is the exploration of structural diversity, as diverse structures can lead to diverse biological activities and mechanisms of action. This review delves into the role of structural diversity in antimicrobial discovery, highlighting its influence on factors such as target selectivity, binding affinity, pharmacokinetic properties, and the ability to overcome resistance mechanisms. We discuss various approaches for exploring structural diversity, including combinatorial chemistry, diversity-oriented synthesis, and natural product screening, and provide an overview of the common mechanisms of action of antimicrobials. We also describe techniques for investigating these mechanisms, such as genomics, proteomics, and structural biology. Despite significant progress, several challenges remain, including the synthesis of diverse compound libraries, the identification of active compounds, the elucidation of complex mechanisms of action, the emergence of AMR, and the translation of laboratory discoveries to clinical applications. However, emerging trends and technologies, such as artificial intelligence, high-throughput screening, next-generation sequencing, and open-source drug discovery, offer new avenues to overcome these challenges. Looking ahead, we envisage an exciting future for structural diversity-oriented antimicrobial discovery, with opportunities for expanding the chemical space, harnessing the power of nature, deepening our understanding of mechanisms of action, and moving toward personalized medicine and collaborative drug discovery. As we face the continued challenge of AMR, the exploration of structural diversity will be crucial in our search for new and effective antimicrobials.

Asymmetric Allylation of Aldoxime Derivatives with β‐Amidoallylboronate in Water and Its Application to Divergent Synthesis of N‐Hydroxy‐γ‐Lactam and 1,2‐Oxazinan‐6‐one

AbstractA new application involving a water–stable amido–functionalized allylboronate has been developed for 1,2‐addition to carbon–nitrogen double bonds. The process achieves highly enantioselective allylation of aldoxime derivatives in water, by employing O‐Boc oximes as substrates under Zn(OH)2–chiral aminophenol catalysis. This process affords the corresponding homoallylic amines with 91–96 % ee. The products could be transformed into N‐hydroxy‐γ‐lactam or 1,2‐oxazinan‐6‐one, through an acidic or a protection‐acidic treatment sequence, respectively, almost without enantiopurity loss.

Iodine-Catalyzed Diversity-Oriented Synthesis of 3,4-Heterocycle-Fused Coumarins from 4-Aminocoumarins and Aurones in Different Solvent.

An unprecedented protocol has been developed for the synthesis of 3,4-heterocycle-fused coumarins from 4-aminocoumarins and aurones through iodine-catalyzed cascade reactions. Dihydropyridine-fused coumarin, pyridine-fused coumarin, and pyrrole-fused coumarin derivatives were achieved in good yields with high selectivity when CH3CN, AcOH, and DMSO were used as the solvent, respectively. This protocol provides several advantages, such as easily available starting materials, high atom economy, friendly environment, and simple procedure.